A group of researchers from The Scripps Research Institute
and Novartis Pharma AG have been awarded a $3.45 million grant
to collaborate on the design of new ways to treat depression
and nicotine addiction.

The grant, titled "Development of GABAB
compounds for depression and smoking," was funded jointly
by two of the agencies within the National Institutes of Heath,
the National Institute of Mental Health (NIMH), which contributed
80 percent, and the National Institute on Drug Abuse (NIDA),
which contributed 20 percent.

"We are very excited about this opportunity," says Athina
Markou, who is associate professor at Scripps Research and
the director of the overall collaborative project. "It will
allow us to focus on drug discovery for depression and nicotine
dependence in a way that neither Scripps nor Novartis could
accomplish on their own."

Issuing collaborative grants jointly to academic research
institutes and pharmaceutical companies is a strategy that
other NIH institutes, such as the National Cancer Institute
and the National Institute for Allergy and Infectious Diseases,
have used successfully and one that the NIH is encouraging,
according to the recent NIH Roadmap. The Scripps ResearchNovartis
Pharma AG grant was made through a new funding mechanism called
the "National Cooperative Drug Discovery Group for the Treatment
of Mood Disorders or Nicotine Addiction" and marks the first
time the neurosciences institutes (NIMH and NIDA) have funded
a public-private partnership in drug discovery.

Depression and Suicide

A widespread medical problem, depression is an often debilitating
psychiatric condition marked by persistent feelings of sadness
or hopelessness, inactivity, changes to sleep and eating patterns,
and suicidal tendencies. Doctors as far back as Hippocrates
recognized the problems of depression and have sought ways
to treat it.

NIMH estimates that, in any given year, about one out of
every ten American adults suffers some form of major depression,
and the World Health Organization estimates the annual cost
of depression in the United States exceeds $43.7 billion.
About two percent of all Americans will use antidepressants
at some point in their lives.

One of the core symptoms of serious depression is suicidal
tendencies. In 2000, according to the National Center for
Injury Prevention and Control (NCIPC), 29,350 Americans committed
suicide, making it the eleventh leading cause of death in
the United States that year. In fact, in 2000, many more people
died from suicide than homicide.

Depression is defined by a number of symptoms that have
been well recognized and described by doctors for years, and
doctors can diagnose and treat depression in patients based
on these symptoms. But the disease is highly variable and
manifests itself differently from person to person. On the
neurobiological level, the disease is not well understood.
Are genes being turned on and off to fuel depression? Are
neurons rewiring? Are neurons secreting more or less of neurotransmitters
at particular brain sites? Which sites? We simply do not know.

Today there are a number of drugs for treating for depression,
but they are not a panacea. Treatment characteristically takes
six to eight weeks to kick in, and as many as a third of patients
do not respond to any antidepressant. New ways to treat depression
are needed. Given the risk of suicide for patients beginning
medication, a quick-acting compound for the treatment of depression
would be a great boon.

"That would be an absolutely major advance and would save
many lives," says Paul Herrling, who is head of Corporate
Research at Novartis International and who has many years
of experience with drug discovery and academia-industry collaborations.

GABA and Depression

The grant is based on evidence that there are mechanisms
of depression that have not yet been targeted by therapeutics.
This system revolves around a neurotransmitter called gamma-aminobutyric
acid (GABA) and the cell receptors to which it binds.

GABA is one of the major inhibitory neurotransmitters in
the braina chemical that carries a signal from one neuron
to another. GABA is released by certain neurons into a synapse
or gap between two neurons, and it diffuses across this gap
and binds to GABA receptors on the adjacent neuron.

The TSRI and Novartis teams will be looking at the role
of GABA in depression and will be exploring the hypothesis
that increasing GABA transmission will have a beneficial effect
on depression.

Novartis has developed some compounds that enhance GABA
neurotransmission, and Markou and her colleagues at Scripps
Research will be testing them, hoping to identify one or more
that have a measurable effect on depression.

The work will be split between Novartis and Scripps Research,
and will involve frequent interaction, visits to each other's
sites, and joint publications. Novartis will conduct the molecular
biology studies of the GABA receptor system, the medicinal
chemistry of GABA positive modulators, and the traditional
aspects of drug discovery and design. Scripps Research will
focus on behaviorally testing the compounds Novartis produces.
The behavioral testing will be conducted in existing models
of depression and nicotine dependence, and both the Novartis
and the Scripps Research teams will also focus on developing
new behavioral models of depression. New models of depression
are desperately needed in this field, and the NIMH, recognizing
the limitations of the current models, has encouraged the
development of a new model by making it an explicit goal.

The Novartis portion of the grant will be led by John Cryan
at Novartis Pharma AG. Cryan will lead the behavioral pharmacology
work at Novartis, and Klemens Kaupmann and Wolfgang Froestl,
two other scientists at Novartis Pharma AG in Basel, will
build on their respective experience in GABAB
receptor pharmacology and medicinal chemistry to focus on
this receptor as a therapeutic target in nicotine dependence.
Finally, Graeme Bilbe, head of the Disease Area Neuroscience
at Novartis Pharma AG, will be a collaborator on this grant
on the Novartis site, and will advise the team on drug discovery
issues.

"I am thrilled that we will be able to work with such an
outstanding and experienced multidisciplinary team of Novartis
researchers," says Markou. "And I am also very grateful that
Dr. Bilbe has agreed to assist us with this project. His support
and input will be very valuable."

Nicotine and GABA Another goal of the grant is to look at
the connection between cigarette smoking and depression, which
could shed light on what makes nicotine so addictive, and
how these same sorts of compounds could be used to treat nicotine
addiction.

Smoking is a major health problem in the United States,
and, according to the U.S. Centers for Disease Control and
Prevention, hundreds of thousands of Americans die each year
from smoking-related lung cancer, ischemic heart disease,
and chronic airway obstruction.

Markou has been working for several years in the area of
drug dependence and withdrawal and has found evidence of depression-like
states in withdrawal from amphetamines and from nicotine.
In other words, those who are trying to quit smoking often
experience depressionsometimes severeand tobacco
use may be higher among people suffering from depression because
they are using it to self-medicate depressive symptoms.

"Fifty percent of depressed people smoke, versus thirty
percent in the general population," says Markou.

This observation is bolstered by clinical evidence that
treating people for depression during smoking cessation can
help them quit smoking. In fact, one type of antidepressant
is approved by the U.S. Food and Drug Administration (FDA)
for use in smoking cessationthe only non-nicotine based
therapy for smoking cessation approved by the FDA.

There is also strong evidence in the scientific literature
that GABA is involved in nicotine addiction, just as it is
in depression. If you increase GABA transmission, then the
rewarding effects of nicotine decrease. For instance, if scientists
block the enzyme that breaks down GABA, resulting in more
GABA around in the synapse, or if they activate GABA receptors
through the administration of agonist drugs, nicotine self-administration
decreases.

An increase of GABA may lead to a general blocking of some
of the positive effects of nicotine, like the accumulation
of dopamine in the nucleus accumbensone of the so-called
pleasure centers of the brain.

While the grant is focused primarily on depression, it is
also funding research on nicotine dependence. The TSRI scientists
will conduct experiments to determine whether the compounds
Novartis produces block the reinforcing aspects of nicotine
use and/or reduce the negative aspects of nicotine withdrawal
that may have phenomenological and neurobiological similarities
with symptoms of depression.

Towards Further Collaborations

The recently funded grant is an experiment of sorts itself.

It is designed to foster a collaborative approach aimed
at developing new medicines to treat depression by bringing
together scientists in an academic research institute such
as Scripps Research with their counterparts in industrial
pharmaceutical laboratories such as those at Novartis Pharma
AG.

The grant is the first of its kind for NIDA and NIMH, and
may become a free-standing program if this sort of collaboration
proves to be a good model for stimulating drug discovery at
the National Institutes of Health.

The idea is part of the National Institutes of Health's
new roadmap to create these sorts of publicprivate partnerships
and collaborations, combining the strengths of academic laboratories
with those of pharmaceutical companies.

The idea behind a collaborative grant between an academic
research institute, such as Scripps Research, and a pharmaceutical
company, like Novartis Pharma AG, is that it could speed up
the identification of new and high-risk targets for drug developmentin
this particular case, a new class of drugs for treating depression
that would hopefully act differently than the traditional
tricyclics or selective serotonin reuptake inhibitors.

In general, the idea of this sort of collaboration between
academic laboratories and pharmaceutical companies is that
if a drug candidate shows promise, then a pharmaceutical company
collaborator might devote resources towards getting them into
trials much sooner than they otherwise would. The hope is
that this will bring promising lead compounds into clinical
testing more rapidly.

One of the benefits of the grant is that it is designed
so that certain molecules that are developed as part of the
grant, but which are not pursued further as drug candidates,
will be placed in the public sector where they can serve as
starting points for further basic research and drug discovery
in the scientific community at large.

Part of the National Institutes of Health's roadmap calls
for the creation of a library of small molecules available
to public sector biomedical researchers. These could be used
as chemical probes to study cellular pathways in greater depth,
providing new ways to explore the functions of major components
of the cell in health and disease and accelerating the development
of promising new drugs, especially for rare diseases.

Markou and the scientists at Scripps Research will test
the compounds that Novartis generates for efficacy in several
behavioral pharmacology models of depression.

Another public benefit will be that this research may generate
new models of depression. Markou has been working for several
years in this area and is hoping to validate new models as
part of her work on the grant.

"I'm happy to say that our many years of interaction with
Scripps have led us to the state where we can do this collaboration,"
says Herrling. "This is a perfect collaboration."

"We are very excited about this opportunity,"
says Athina Markou, who is associate professor at Scripps
Research and director of the collaborative project. Photo
by Jason S. Bardi.